The existence of a stimulatory intestinal phase of gastric acid secretion has been suspected, although largely ignored, for many years. Recently, however, the importance of the intestine in the regulation of gastric secretion has been increasingly recognized. The intestinal phase is of additional interest in relation to the profound gastric acid hypersecretion associated with portacaval shunt. Considerable evidence suggests that shunt-related gastric hypersecretion is due to unmasking of the intestinal phase by hepatic bypass of a humoral stimulant in portal blood that is normally degraded substantially by the liver. Studies in our laboratory during the past ten years have provided conclusive physiologic evidence for humoral mediation of both the intestinal phase of gastric secretion and of shunt-related hypersecretion by an endogenous substance (hormone) that arises in the small intestine, particularly in the jejunum. Moreover, our studies have demonstrated that this endogenous substance exists in humans as well as in dogs, rats and pigs. With these physiologic studies as a background, we have used a classical method for extracting acidic peptides to prepare an extract of hog intestinal mucosa that has all known properties of an intestinal phase hormone (IPH). Specifically, the intestinal mucosa extract contains a potent stimulant of gastric acid secretion that acts according to a regular dose-response relationship, that is not gastrin in any of its immuno-assayable forms, that significantly augments the acid secretory response to maximal stimulating doses of pentagastrin and hog gastrin, and that is substantially degraded by the liver (in contrast to gastrin). It now remains to isolate the IPH in pure form and identify it by the use of biochemical techniques for isolation of peptides combined with testing of fractions for stimulatory activity in reliable bioassay models that we have developed and validated. Furthermore, it remains to determine the mechanism of action, metabolism and range of physiologic effects of the IPH, and to define its role in normal and pathologic gastric acid secretion by appropriate physiologic studies. The proposed research is directed at these objectives.